MECHANISM AND ROLE OF NOVEL CHLAMYDIAL TRANSCRIPTIONAL REGULATOR, CHXR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chlamydiae are human pathogens that cause sterility, blindness, and pneumonia, and are strongly correlated with heart disease, the number one cause of death in humans. Chlamydia are obligate intracellular bacteria and are perpetuated through a defining biphasic developmental cycle that is intimately linked with pathogenesis. The developmental cycle is governed predominately at the transcriptional level; however, there is a critical deficiency in our understanding of developmental regulatory mechanisms in Chlamydia. Identifying these components and characterizing the mechanisms is critical for understanding how Chlamydia interact with the host and eventual generation of novel antimicrobial targets. The long-term goal of our research is to characterize the molecular mechanisms that regulate chlamydial development and pathogenesis. This proposal is designed to determine the structural and functional relationships of a chlamydial transcription factor, ChxR. The central hypothesis is that ChxR is a master regulator of Chlamydia development and the expression of its virulence determinants. ChxR is a 26 kD protein homologous to the well-studied OmpR subfamily of response regulators. Largely due to the current genetic intractability of chlamydiae, the biological role of ChxR is not known. To elucidate the biological role and determine regulatory mechanism of ChxR the following specific aims are proposed: 1) define the direct in vivo gene targets of ChxR, 2) identify the mechanism of ChxR transcriptional activation, and 3) determine the three-dimensional structure of ChxR. As a result of these studies, we expect to address a fundamental question in the field, 'how do Chlamydia regulate their growth?' Furthermore, since response regulators like ChxR are widespread in bacteria and absent in mammals, they are attractive targets for development of new antimicrobials.